The majority of the damage in chronic viral hepatitis has been shown to be due to the host immune reaction. Our understanding of the details of this process is only superficial, due in large part to a lack of convenient animal models of human disease. To address this problem, we propose to develop suitable models of human hepatitis viral infections based on rats with normal immune systems. To accomplish this, we propose to use a technique to induce immunological tolerance to the presence of human hepatocytes in host rats, and provide a selective survival advantage to permit human hepatocytes to proliferate and repopulate the host liver in preference to endogenous rat hepatocytes. Immune tolerance to human hepatocytes, recently has been demonstrated using intrafetal injections of human cells. Subsequent transplantation of the same cells resulted in survival and function of relatively low numbers of cells. To increase the numbers, in vivo selecth the hepatocyte- selective targeting due to the presence of asialoglycoprotein receptors selectively on the plasma membrane of mammalian hepatocytes. 2) HSV-thymidine kinase transgenic rats will be prepared, in which the homozygotes will develop endogenous hepatocyte elimination due to the genetic defect. The anticipated result will be animals whose livers consist predominantly of functional human hepatocytes in controlled and predictable numbers which survive in rats that are not immunosuppressed or immunodeficient. The numbers of surviving human liver cells will be quantitated, and the conditions required to generate specific ratios of human to rat cells determined. To demonstrate function, human liver-specific protein secretion will be measured. HCV infections will be characterized by quantitative RNA in serum and liver, negative strand-specific real-time PCR to detect replication in liver, HCV protein in liver by immunohistochemistry, and antibodies to HCV proteins in serum. Hthe model could be useful in the study of other difficult problems such as autoimmune reactions to drugs, effects of immunomodulatory agents, and in the study of other liver infections such as malaria. To our knowledge, there is no similar system of its kind, and as such it represents a unique small-animal model, which may be valuable in the study of agent-host cell interactions that cannot be studied in other systems. 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